Small molecule inhibitors of the MCL-1 oncoprotein and uses thereof

Abstract

Compounds that inhibit Myeloid Cell Leukemia-1 (Mcl-1) oncoprotein, and methods of using the same, are provided for treating disease.

What is claimed is: 
     
       1. A compound comprising formula (II): 
       
         
           
           
               
               
           
         
         wherein each R 21  and R 22  can independently represent a substituent selected from the group consisting of H and optionally substituted alkyl and aryl; 
         A 21  is a substituent selected from the group consisting of S(═O), S(═O) 2 , and C(═O); 
         X 21  is CH; 
         each Z 21  can independently represent a substituent selected from the group consisting of H, halo, cyano, hydroxy, nitro, and optionally substituted acylsulfonamide, alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkynyl, alkenyl-cycloalkyl, alkynyl-cycloalkyl, carbonyl, carboxaldehyde, carboxyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amino, amido, aryl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxamate, sulfanyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, and sulfonate; 
         Y 21  is a substituent selected from the group consisting of —C(O)O—, —CONR 22 —, —CONR 22 —SO 2 —, —CONR 22 O—, 
       
       
         
           
           
               
               
           
         
         R 23  and R 24  each independently represents a substituent selected from the group consisting of optionally substituted alkyl and aryl; and R 23  and R 24  can, taken together, comprise an optionally substituted cycloalkyl or heterocycloalkyl ring; 
         pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
       
     
     
       2. The compound of  claim 1 , wherein the compound is
 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid, 
 and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
 
     
     
       3. A method of treating cancer by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
       4. A method of treating cancer by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering to the patient a therapeutically effective amount of one or more compounds selected from the group consisting of:
 4-(N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid, 
 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid, 
 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid, 
 methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate, 
 methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate, 
 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid, 
 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid, 
 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid, 
 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid, 
 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid, 
 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid, 
 methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, 
 acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, 
 and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
 
     
     
       5. A method of treating cancer by inhibiting Mcl-1 protein activity in a patient in need of said treatment, the method comprising administering to the patient a therapeutically effective amount of one or more compounds selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       6. The method of  claim 3 , wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. 
     
     
       7. The method of  claim 5 , wherein the cancer is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. 
     
     
       8. A pharmaceutical composition for treating cancer by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       9. The compound of  claim 1 , wherein the compound is 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)sulfamoyl)-1-hydroxy-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       10. The compound of  claim 1 , wherein the compound is 1-hydroxy-4-((4-phenylpiperazin-1-yl)sulfonyl)-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       11. The compound of  claim 1 , wherein the compound is methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoate, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       12. The compound of  claim 1 , wherein the compound is methyl 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoate, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       13. The compound of  claim 1 , wherein the compound is 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-methoxy-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       14. The compound of  claim 1 , wherein the compound is 1-hydroxy-4-(piperidin-1-ylsulfonyl)-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       15. The compound of  claim 1 , wherein the compound is 4-(N,N-dimethylsulfamoyl)-1-hydroxy-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       16. The compound of  claim 1 , wherein the compound is 4-((4-benzylpiperazin-1-yl)sulfonyl)-1-hydroxy-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       17. The compound of  claim 1 , wherein the compound is 4-(N-(4-bromophenyl)-N-isobutylsulfamoyl)-1-hydroxy-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       18. The compound of  claim 1 , wherein the compound is 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoic acid, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       19. The compound of  claim 1 , wherein the compound is methyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
     
     
       20. The compound of  claim 1 , wherein the compound is acetoxymethyl 1-hydroxy-4-(N-isobutyl-N-(4-isopropoxyphenyl)sulfamoyl)-2-naphthoate, and the pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof.